Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model.

PURPOSE: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. METHODS: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. RESULTS: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. CONCLUSION: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

Evaluation of pharmacokinetic target attainment and hematological toxicity of linezolid in pediatric patients.

BACKGROUND: Linezolid is commonly used to treat severe and/or resistant Gram-positive infections. Few studies have assessed its pharmacokinetic (PK) target attainment in pediatrics. OBJECTIVE: To evaluate the percentage of pediatrics achieving the PK targets of linezolid with standard dosing regimens and to assess the incidence and risk factors associated with its hematologic toxicity. METHODS: This prospective observational study included pediatric patients aged 0-14 who received linezolid for suspected or proven Gram-positive infections. Linezolid trough concentrations and the 24-h area under the curve (AUC24) were estimated, and hematologic toxicity was assessed. RESULTS: Seventeen pediatric patients (5 neonates and 12 older pediatrics) were included. A wide variability was observed in linezolid's trough and AUC24 (ranging from 0.5 to 14.4 mg/L and from 86 to 700 mg.h/L, respectively). The median AUC24 was significantly higher in neonates than older pediatrics (436 [350-574] vs. 200 [134-272] mg,h/L, P = 0.01). Out of all patients, only 41% achieved adequate drug exposure (AUC24 160-300 mg.h/L and trough 2-7 mg/L), with 24% having subtherapeutic, and 35% having higher-than-optimal exposures. Hematological toxicity was observed in 53% of cases. Identified risk factors include treatment duration over 7 days, baseline platelet counts below 150 × 109/L, sepsis/septic shock, and concomitant use of meropenem. CONCLUSIONS: Linezolid's standard dosing failed to achieve its PK targets in approximately half of our pediatric cohort. Our findings highlight the complex interplay between the risk factors of linezolid-associated hematological toxicity and underscore the importance of its vigilant use and monitoring, particularly in pediatrics with concomitant multiple risk factors.

Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients.

PURPOSE: To assess the pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of hospitalized Chinese older patients. METHODS: Patients > 60 years of age, who received intravenous linezolid (600 mg), were included. A population pharmacokinetics (PPK) model was established using nonlinear mixed-effects modeling. The predictive performance of the final model was assessed using goodness-of-fit plots, bootstrap analyses, and visual predictive checks. Monte Carlo simulations were used to evaluate the achievement of a pharmacodynamics target for the area under the serum concentration-time curve/minimum inhibitory concentration (AUC0-24/MIC). RESULTS: A total of 210 samples were collected from 120 patients. A one-compartment PPK model with linear elimination best predicted the linezolid plasma concentrations. Linezolid clearance (CL) was 4.22 L h-1 and volume of distribution (Vd) was 45.80 L; serum uric acid (SUA) was a significant covariate of CL. CONCLUSION: The results of this study indicated that the standard dose was associated with a risk of overexposure in older patients, particularly those with high SUA values; these patients would benefit from a lower dose (300 mg every 12 h).

Prolonged infusion of linezolid is associated with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles in patients with external ventricular drains.

OBJECTIVE: We previously investigated the pharmacokinetic and pharmacodynamic (PK/PD) parameters of routine linezolid infusions (1 h) in patients with external ventricular drains (EVD). The aim of the study was to determine whether extended linezolid infusions (200 mg/h for 3 h) were more efficacious than short linezolid infusions (600 mg/h for 1 h). METHODS: We collected cerebrospinal fluid (CSF) and plasma samples from 10 patients who received linezolid infusions after cerebral hemorrhage surgery with EVDs. Linezolid concentrations were measured by high-performance liquid chromatography (HPLC). A Monte Carlo simulation was used to measure the probability of target attainments (PTA) and the PK/PD indexes at four minimum inhibitory concentrations (MIC). RESULTS: When the same dose (600 mg) was given as an extended infusion (3 h), linezolid reached its maximum concentrations in the plasma and CSF at 3.00 h and 4.40 h, respectively. The mean penetration of linezolid in CSF was 41.31%. Using the parameter of AUC0-24 h/MIC ≥ 100, the plasma PTA provided good coverage at > 90% when MIC was ≤ 1 µg/mL, while the values were 0 in CSF. Using the parameter %T (time) > MIC ≥ 85%, the PTA in both the plasma and CSF provided good coverage when MIC ≤ 2 µg/mL. Compared with routine infusions, prolonged infusion times (3 h) showed increased PTA of linezolid. CONCLUSIONS: Prolonged infusion times increased the concentration of linezolid in the plasma, leading to improved therapeutic outcomes. However, this improvement did not exist in CSF. Lastly, the PK/PD indicator AUC/MIC ≥ 100 may be used to achieve improved outcomes in patients with critical infections.

Analysis of the risk factors of linezolid-related haematological toxicity in Chinese patients.

WHAT IS KNOWN AND OBJECTIVES: Haematological toxicity including thrombocytopenia, anaemia and leucopenia is the main adverse events of linezolid (LZD) therapy. This study aimed to investigate the risk factors for LZD-induced haematological toxicity and define the threshold of plasma trough concentration to minimize the haematological toxicity. METHODS: 145 patients who received LZD for more than 10 days were retrospectively reviewed to determine the incidence of LZD-induced haematological toxicity. Meanwhile, the risk factors of haematological toxicity were confirmed by univariate and multivariate logistic regression analysis. RESULTS AND DISCUSSION: 9 (6.2%) patients developed leucopenia, while 52 (35.9%) and 26 (17.9%) patients developed thrombocytopenia and anaemia, respectively. The estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2 (OR, 2.744; 95% CI, 1.117-6.734; p = 0.028) and baseline platelet count <200 × 109 /L (OR, 6.817; 95% CI, 2.870-16.193; p < 0.0001) were found to be significant risk factors for LZD-related thrombocytopenia. Aspartate aminotransferase (AST) >80 U/L (OR, 4.844; 95% CI, 1.207-19.451; p = 0.026) and eGFR <90 ml/min/1.73 m2 (OR, 7.132; 95% CI, 2.088-24.357; p = 0.002) were the risk factors for LZD-related anaemia. However, no significant risk factors were identified for LZD-related leucopenia. Moreover, LZD plasma trough concentration >8 mg/L [OR, 3.047; 95% CI, 1.233-7.539; p = 0.016] could be a predictor for the development of thrombocytopenia and anaemia. WHAT IS NEW AND CONCLUSION: Hepatic and/or renal dysfunction are the risk factors for LZD-related haematological toxicity, while the target plasma trough concentration within 8 mg/L via dose reduction could minimize the haematological toxicity induced by LZD.

A sensitive and high-throughput quantitative liquid chromatography high-resolution mass spectrometry method for therapeutic drug monitoring of 10 ß-lactam antibiotics, linezolid and two ß-lactamase inhibitors in human plasma.

An ultra-high pressure liquid chromatography high-resolution mass spectrometric (UHPLC-HRMS) method was developed for the simultaneous and sensitive quantification of 10 ß-lactam antibiotics (cefepime, meropenem, amoxicillin, cefazolin, benzylpenicillin, ceftazidime, piperacillin, flucloxacillin, cefuroxime and aztreonam), linezolid and ß-lactamase inhibitors tazobactam and clavulanic acid in human plasma. Validation according to the EMA guidelines showed excellent within- and between-run accuracy and precision (i.e. between 1.1 and 8.5%) and high sensitivity (i.e. lower limit of quantification between 0.25 and 1 mg/L). The UHPLC-HRMS method enables a short turnaround time and high sensitivity and needs only a small amount of plasma, allowing appropriate routine therapeutic drug monitoring. The short turnaround time is obtained by speeding up the protocol on multiple levels, i.e. fast and workload-efficient sample preparation (i.e. protein precipitation and dilution), short (4 min) instrument run time, simultaneous measurement of all relevant ß-lactam antibiotics used in the intensive care unit and the use of the same instrument, column and mobile phases as for the other routine methods in our laboratory.

Accumulation of Major Linezolid Metabolites in Patients with Renal Impairment.

In patients with renal impairment (n = 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.

Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study.

BACKGROUND: Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO. METHODS: Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints. RESULTS: The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem. CONCLUSIONS: ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

Long-Term Effects on QT Prolongation of Pretomanid Alone and in Combinations in Patients with Tuberculosis.

Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. Three heart rate corrections to QT were considered: Fridericia's QTcF, Bazett's QTcB, and a population-specific correction, QTcN. QTc increased with the plasma concentrations of pretomanid, bedaquiline's M2 metabolite, and moxifloxacin in a manner described by a linear model in which the three slope coefficients were constant across studies, visits within study, and times postdose within visit but where the intercept varied across those dimensions. The intercepts tended to increase on treatment to a plateau after several weeks, a pattern termed the secular trend. The slope terms were similar for the three QTc corrections, but the secular trends differed, suggesting that at least some of the secular trend was due to the elevated heart rates of tuberculosis patients decreasing to normal levels on treatment. For pretomanid 200 mg once a day (QD) alone, a typical steady-state maximum concentration of drug in plasma (Cmax) resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% confidence interval (CI) limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The contribution to these values from the secular trend was 4.0 ms.

Ultrahigh-throughput absolute quantitative analysis of linezolid in human plasma by direct analysis in real time mass spectrometry without chromatographic separation and its application to a pharmacokinetic study.

Therapeutic drug monitoring (TDM) is necessary in the clinical management of linezolid to improve its efficacy and reduce the risk of time- and dose-dependent toxicity. A novel and ultrahigh-throughput analytical method for the determination of linezolid in human plasma was developed based on direct analysis in real-time tandem mass spectrometry (DART-MS/MS) without chromatographic separation. After solid-phase extraction with Waters Oasis HLB, the linezolid and internal standard linezolid-d3 were detected by positive ion electrospray ionization followed by multiple reaction monitoring (MRM) of the transition at m/z 338.1 → 296.2 and 341.2 → 297.3, respectively. The use of DART-MS obviates the need for chromatographic separation and allowed determination of linezolid in a total run time of only 24 s per sample. The method was linear in the concentration range 0.20-25 µg mL-1 with intraday and interday precision <14.5% and accuracy ranging from -3.85% to 12.7%. The method was successfully applied to a pharmacokinetic study of linezolid in healthy male volunteers after oral administration of a 600 mg tablet. DART-MS/MS provides a rapid and sensitive method for the determination of linezolid that does not require chromatographic separation. It is eminently suitable to meet the high-throughput challenge of clinical TDM. Graphical abstract.

Measurement of Linezolid and Its Metabolites PNU-142300 and PNU-142586 in Human Plasma Using Ultra-Performance Liquid Chromatography Method.

An ultra-performance liquid chromatography (UPLC) method was developed and validated for the quantification of linezolid, PNU-142300, and PNU-142586 in human plasma. After protein precipitation using acetonitrile, the protein-free supernatant was separated using reverse-phase chromatography using an ACQUITY UPLC HSS T3 column and monitored at 254 nm. p-Toluic acid was used as the internal standard. No interference peak was observed at the retention times of linezolid, PNU-142300, PNU-142586, and p-toluic acid from blank plasma. The calibration curve of linezolid was linear from 0.2 to 50.0 µg/mL (coefficient of determination (r2) > 0.9999) and those of PNU-142300 and PNU-142586 were linear from 0.2 to 20.0 µg/mL (r2 > 0.9996 and > 0.9998, respectively). The intra- and inter-assay accuracy (%) and precision (relative standard deviation (RSD) %) of the three components were confirmed to meet the criteria of the U.S. Food and Drug Administration guidelines. Tests confirmed the stability of linezolid, PNU-142300, and PNU-142586 in plasma during three freeze-thaw cycles and long-term storage of frozen plasma for up to 30 d; in extracts they were stable in the UPLC autosampler for over 48 h at 4°C. Furthermore, plasma concentrations of linezolid, PNU-142300 and PNU-142586 in patients treated with linezolid could be measured using the UPLC method developed in this study. This assay would be a powerful tool for therapeutic drug monitoring and clinical pharmacokinetic/pharmacodynamic (PK/PD) analyses in the optimization of linezolid treatment.

Voltammetric monitoring of linezolid, meropenem and theophylline in plasma.

Treatment of healthcare associated Pneumonia (HCAP) caused by Methicillin-resistant Staphylococcus aureus (MRSA) requires therapeutic protocols formed of linezolid (LIN) either alone or in combination with meropenem (MERO) and theophylline (THEO). The inter-individual pharmacokinetic variations require the development of reliable therapeutic drug monitoring (TDM) tools especially in immunocompromised patients. A sensitive square wave voltammetric sensor using multiwalled carbon nanotubes (MWCNTs) modified carbon paste electrode in Britton-Robinson buffer was developed and validated. Experimental parameters such as pH, percentage of MWCNTs, and pre-concentration time were optimized. The sensor was employed at pH 11.0 for the determination of LIN in plasma within a concentration range of 2.5 × 10-8 - 8.0 × 10-6 mol L-1without interference from co-administered medications. On the other hand, simultaneous monitoring of LIN, MERO and THEO in plasma was feasible at pH 3.0 over concentration ranges of 4.0 × 10-7- 9.0 × 10-5, 8.0 × 10-7- 9.0 × 10-5 and 8.0 × 10-7 - 9.0 × 10-5 mol L-1, respectively. The performance of the proposed sensor was validated and the applicability for TDM has been demonstrated in plasma of healthy volunteers.

A Common mdr1 Gene Polymorphism is Associated With Changes in Linezolid Clearance.

BACKGROUND: Several factors contribute to the high variability of linezolid plasma exposure in patients. Very recently, it has been suggested that linezolid could be an ABCB1 substrate. Therefore, the present clinical study was aimed at investigating whether ABCB1 polymorphisms could predict linezolid pharmacokinetics in 27 critically ill patients. METHODS: Genotypes were assessed through a real-time polymerase chain reaction allelic discrimination system, and linezolid plasma concentrations, considering trough concentration (Ctrough) and area under the time-concentration curve (AUC), were analyzed through a nonlinear mixed-effects modeling approach. RESULTS: A significant effect of abcb1 c.3435C>T polymorphism on linezolid clearance was found, whose values accounted for 13.19 L/h in wild-type homozygotes and 7.82 L/h in the remaining individuals. That difference was statistically significant despite the large interindividual variability (60.8%). Terminal half-life and volume of distribution values significantly differed between c.3435CC and c.3435CT/TT patients (2.78 versus 5.45 hours and 37.43 versus 46.71 L, respectively). On the contrary, a modest trend was observed for the difference in AUC and Ctrough based on c.3435C>T genotypes. Simulation according to the final model revealed that the cumulative response fraction for the AUC/MIC parameter was better for .3435CC individuals compared with individuals carrying at least one c.3435T allele with respect to methicillin-sensitive S. aureus, methicillin-resistant S. aureus, and Streptococcus pneumoniae species. CONCLUSIONS: The obtained results suggest the possible influence of ABCB1 in linezolid pharmacokinetics, bringing new interest for pharmacogenetic analyses in antimicrobial chemotherapy. These analyses could be incorporated in therapeutic protocols for precision medicine, including a combined use of genetic evaluation (for starting dose) and follow-up therapeutic drug monitoring.

Comparison of the ARK Immunoassay With High-Performance Liquid Chromatography With Ultraviolet Detection for Therapeutic Drug Monitoring of Linezolid.

BACKGROUND: An enzymatic immunoassay is under development by ARK Diagnostics, Inc for the quantification of plasma concentrations of linezolid (LZD). In this study, the authors aimed to assess the performance of this immunoassay using a validated high-performance liquid chromatography (HPLC) ultraviolet method as reference. METHODS: Within- and between-day in vitro inaccuracy and imprecision of the ARK LZD assay were firstly tested using spiked quality controls (QC) provided by the kit manufacturer. Subsequently, the performance of the immunoassay was verified in vivo by analyzing 170 trough LZD plasma samples from patients on antibiotic therapy. RESULTS: Imprecision of the spiked QCs resulted in every instance less than 7.0% and the inaccuracy ranged from -1.5% to 6.6%. The linear correlation between the 2 methods was documented by the Pearson analysis of plasma samples from patients on LZD therapy (coefficient = 0.9619). By Bland-Altman comparison, 8.2% of the patient samples resulted out of the limits ranging from -27.0% to +33.5%, with most of them having LZD concentrations exceeding 10 mg/L. CONCLUSIONS: Acceptable analytical performance of the ARK LZD immunoassay has been demonstrated both with spiked QC and patients' samples, making it a viable alternative to HPLC for the therapeutic drug monitoring of LZD in clinical practice in laboratory hospitals that do not have HPLC equipment.

Early linezolid-associated lactic acidosis in a patient with Child's class C liver cirrhosis and end stage renal disease.

Linezolid, an oxazolidinone antibiotic, does not required dose adjustment in patients with Child's class A and B liver cirrhosis. The dose adjustment data for Child's class C liver cirrhosis is inadequate. We reported a case of Child's class C liver cirrhosis, in which lactic acidosis, an adverse effect related to prolonged use, occurred only after two weeks of linezolid treatment. A 63-year old male had underlying diseases, such as end-stage renal disease (ESRD) and Child's class C liver cirrhosis, and was admitted for hepatic encephalopathy management and liver transplantation evaluation. Spontaneous bacterial peritonitis and septic shock occurred during admission. Because ascites culture revealed vancomycin-resistant Enterococci (VRE), daptomycin was initially prescribed. Subsequently, VRE bacteremia occurred, and infective endocarditis was confirmed. Following treatment failure with daptomycin use, intravenous linezolid (600 mg q12h) was added for synergic effect. VRE bacteremia quickly resolved following linezolid treatment, and vasopressor use was reduced. Despite stable hemodynamics, lactic acidosis still persisted, and linezolid therapeutic drug monitoring was ordered. High linezolid trough concentration (49 mg/L) was found by therapeutic drug monitoring, and linezolid-associated lactic acidosis was highly suspected. Therefore, linezolid treatment was stopped and patient's lactic acid level returned to normal after one week. VRE bacteremia recurred after discontinuation of linezolid; therefore, linezolid was re-prescribed at the lower dose (600 mg). Linezolid trough concentration was within the therapeutic range this time (6.1 mg/L), and lactic acidosis did not occur when linezolid dose was reduced. Therefore, empirically decreased dose and therapeutic drug monitoring should be considered in patients with Child's class C liver cirrhosis and ESRD.

Systematic Therapeutic Drug Monitoring for Linezolid: Variability and Clinical Impact.

Linezolid serum trough (Cmin) and peak (Cmax) levels were determined prospectively in 90 patients. Adequate exposure was defined as a Cmin of 2 to 8 mg/liter. Therapy was empirical (73.3%) or targeted (26.7%). Wide interindividual variability in linezolid Cmin levels was recorded (0.1 to 25.2 µg/ml). Overall, 65.5% of the patients had out-of-range, 41.1% had subtherapeutic, and 24.4% had supratherapeutic trough levels. We did not find a correlation between abnormal levels and adverse events, in-hospital mortality, or overall poor outcome.

Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult Subjects.

A multipart phase 1 study was conducted to determine the safety, tolerability, pharmacokinetics, and food effect of the novel oral oxazolidinone, MRX-I, in healthy adults, as well as the tolerability of longer-term exposure of both oral MRX-I and linezolid. Thirty subjects in part 1 received single ascending doses of MRX-I or placebo under fasting or fed condition in a double-blind crossover design. Twelve subjects in part 2 received MRX-I at 800 mg every 12 h (q12h) for 14 days in a double-blind, placebo-controlled design. In part 3, 24 subjects were randomized to receive 28 days of MRX-I at 800 mg q12h or oral linezolid at 600 mg q12h for 28 days in a double-blind, double-dummy design. Oral MRX-I was associated with a greater bioavailability and exposure when administered with food, and minimal accumulation of MRX-I occurred after multiple-dose administration. Oral MRX-I was well tolerated at single doses of up to 1,200 and 800 mg q12h for up to 28 days; all adverse events were mild to moderate in severity, and there was no drug discontinuation due to adverse events. These data support further clinical development of oral MRX-I in the treatment of resistant Gram-positive bacterial infections.

Penetration of linezolid into synovial fluid and muscle tissue after elective arthroscopy.

Objectives: Penetration of antibiotics into synovial fluid is crucial to combat septic arthritis efficiently. Since linezolid may be used for treatment of septic arthritis when methicillin-resistant bacterial strains are suspected, we investigated its target-site concentrations in synovial fluid. Patients and methods: Ten patients undergoing elective knee arthroscopy were included in this study. Subjects received a single dose of 600 mg of linezolid intravenously and linezolid concentrations were measured in plasma and by using microdialysis in muscle tissue and synovial fluid. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing ability were performed using CLSI breakpoints and MIC90 for clinical isolates. Results: All 10 subjects tolerated linezolid well. As indicated by AUCtissue/AUCfree plasma ratios of 0.76 ±âŸ0.34 (synovial fluid) and 0.98 ±âŸ0.62 (muscle tissue) linezolid penetrated well into the knee gap and tissue. In synovial fluid AUC0-24/MIC ratios for bacteria with an MIC of 1, 2 and 4 mg/L were 86.8 ±âŸ47.0, 43.4 ±âŸ23.5 and 21.7 ±âŸ11.8, respectively. Conclusions: Linezolid may be used to treat septic arthritis caused by bacterial strains with an MIC ≤1 mg/L. Assuming a pharmacokinetic/pharmacodynamic target of > 50 for AUC0-24/MIC, when treating strains with an MIC >1 mg/L treatment surveillance is warranted. However, pharmacokinetic/pharmacodynamic targets for tissue are poorly understood and clinical data are needed to verify our assumptions.

Comparative effectiveness of linezolid versus vancomycin as definitive antibiotic therapy for heterogeneously resistant vancomycin-intermediate coagulase-negative staphylococcal central-line-associated bloodstream infections in a neonatal intensive care unit.

Objectives: Heterogeneously resistant vancomycin-intermediate coagulase-negative staphylococci (hVICoNS) are emerging pathogens causing central-line-associated bloodstream infections (CLABSIs) in neonatal intensive care unit (NICU) patients. Given the burden of disease associated with CLABSI and the current lack of therapeutic guidelines, we aimed to compare the effectiveness of linezolid versus vancomycin used as the definitive antibiotic therapy for hVICoNS CLABSI. Methods: We performed a retrospective cohort study of infants with hVICoNS CLABSI from a single NICU between 2009 and 2014, treated with either linezolid or vancomycin as definitive antibiotic therapy. CLABSI duration, early and late recurrence and in-hospital mortality were compared using propensity score-adjusted proportional hazards and logistic regression models. Results: Of 89 infants with hVICoNS CLABSI, 33 (37.1%) treated with linezolid were compared with 56 (62.9%) treated with vancomycin. The median duration of CLABSI was 5 (range 1-12) versus 4 days (range 0-14) ( P = 0.11), early recurrences were 3.0% versus 7.1% ( P = 0.42), late recurrences 0% versus 14.3% ( P = 0.02) and mortality 27.3% versus 28.6% ( P = 0.90), when treated with linezolid versus vancomycin, respectively. When adjusting using a continuous propensity score, linezolid had an HR of 0.78 (95% CI 0.48-1.27) for CLABSI duration, an OR of 0.23 (95% CI 0.02-2.56) for early recurrence and an OR of 0.9 (95% CI 0.3-2.67) for mortality, relative to vancomycin. Conclusions: There was no statistically significant difference between linezolid and vancomycin when used as definitive treatment for hVICoNS CLABSI in NICU patients, in terms of CLABSI duration, recurrence or all-cause mortality.

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients.

Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n = 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.).